Components of
Participating OrganizationsThis FOA is developed
as a NIH Common Fund/Roadmap initiative. All NIH Institutes and Centers
participate with the NIH Office of the Director in Common Fund/Roadmap initiatives.This FOA will be administered by NIAAA (http://www.niaaa.nih.gov) on behalf of the NIH
(http://www.nih.gov).

Title:Epigenomics of Human Health
and Disease (R01)

Announcement
Type New

Update: The following update relating to this announcement has been issued:

October 3, 2008 - See Notice (NOT-RM-09-001) Clarification of Research Objectives and Review and Selection Process.

Request for
Applications (RFA) Number: RFA-RM-08-017

NOTICE: Applications submitted in response to this
Funding Opportunity Announcement (FOA) for Federal assistance must be submitted
electronically through Grants.gov (http://www.grants.gov) using the SF424 Research and Related (R&R) forms and the SF424
(R&R) Application Guide.

APPLICATIONS MAY NOT
BE SUBMITTED IN PAPER FORMAT.

This FOA must be read
in conjunction with the application guidelines included with this announcement
in Grants.gov/Apply
for Grants (hereafter called Grants.gov/Apply).

A registration process
is necessary before submission and applicants are highly encouraged to start
the process at least four (4) weeks prior to the grant submission date. See Section IV.

Purpose.The National Institutes of Health invites applications
that propose research to transform our
understanding of the epigenetic contributions to human disease. Studies
will characterize global (epigenome-wide) marks or features, and their
possible interactions, in cells and tissues that are representative of
various human disease states, conditions, or
processes. Rather than solely advancing knowledge, “transformation” as
defined in this FOA, is intended to change our fundamental understanding
of human health and disease by creating a new paradigm or by disrupting an existing one. Unbiased epigenome-wide (global)
mapping approaches must be used to identify marks in diseased, aged, or
environmentally compromised human primary cells or tissues. Mammalian
animal models are allowed in rare exceptions where human samples cannot be obtained for a given disease/condition of
interest, but strong justification must be provided. Mapping the epigenome
of normal cells will only be permitted as a control for mapping the
epigenome of diseased or other aberrant cellular states. Studies may also include follow-up epigenetic approaches to
reveal function or significance of target genomic regions or loci
identified through the initial mapping.

Mechanism of Support. This FOA will utilize the R01 grant
mechanism.

Funds
Available and Anticipated Number of Awards.These R01s
may propose a maximum of five years of support. Awards issued under this
FOA are contingent upon the availability of funds and the submission of a
sufficient number of meritorious applications. The anticipated number of awards
is 12-16.

Budget and Project Period. A total of
$8 million in FY 2009 has been committed to support this FOA.

Application Research Plan
Component Length: The R01 application Research Plan
component of the PHS398 may not exceed 12 pages,including tables, graphs,
figures, diagrams, and charts. See
https://grants.nih.gov/grants/funding/funding_program.htm.

Eligible Project Directors/Principal
Investigators (PDs/PIs). Individuals with the skills, knowledge, and
resources necessary to carry out the proposed research are invited to work
with their institution/organization to develop an application for support.
Individuals from underrepresented racial and ethnic groups as well as
individuals with disabilities are always encouraged to apply for NIH
support.

Number of PDs/PIs. More than one PD/PI
(i.e., multiple PDs/PIs) may be designated on the application.

Number of Applications. Applicants
may submit more than one application, provided each application is
scientifically distinct.

Resubmissions. Resubmission applications are
not permitted in response to this FOA.

The
NIH invites qualified investigators from academic or research institutions to
submit an application for this Funding Opportunity
Announcement (FOA) whose goal is to address the Epigenomics of Human Health and
Disease as part of the NIH Roadmap Epigenomics Program.

Epigenetic
processes are critical to the normal development and function of multi-cellular organisms and play an important role in
human disease. This FOA seeks to transform our understanding of the epigenetic
contributions to human disease. The FOA focuses on research to define global
(epigenome-wide) marks or features, and their
possible interactions, in diseased, aged, or otherwise compromised human
primary cells or tissues. These studies may also include follow-up epigenetic
analyses to reveal function or significance of target gene regions or loci
identified through the initial mapping activities.
Characterizing the epigenomic components that may regulate the transcriptional
potential of a cell and contribute to the etiology, severity or progression of
human disease will provide novel insights into disease pathogenesis and therapeutic approaches. This knowledge will enhance our
ability to investigate, diagnose and ameliorate human disease with a
significant epigenetic component.

The
NIH Roadmap is a series of programs designed to foster new ways of doing
research, to fill fundamental knowledge gaps, and to
encourage risk taking to solve complex problems. The overarching criterion for
Roadmap programs is that they are expected to transform the way research is
conducted across the spectrum of health research. The programs in their entirety therefore do not address specific diseases,
although individual awards within a program may be disease-specific (http://nihroadmap.nih.gov/).

There
are five related components of the Roadmap Epigenomics
Program. Four of these have already been announced. The RFA numbers and titles
are as follows: RFA-RM-07-013, Reference Epigenome Mapping Centers
(REMCs); RFA-RM-07-014, Epigenomics Data Analysis and
Coordination Center (EDACC); RFA-RM-07-011
(R01) and RFA-RM-07-012
(R21) Technology Development in Epigenetics; and RFA-RM-07-015
(R01) and RFA-RM-07-016
(R21) Discovery of Novel Epigenetic Marks in Mammalian Cells.
The fifth component, this FOA, addresses the Epigenomics of Human Health and
Disease.

It
is anticipated that research funded by the Roadmap
Epigenomics Program will ultimately have a significant impact on our ability to
promote human health and prevent and treat human disease through the
development of potential biomarkers, therapeutic targets and tissue
regeneration strategies.

Purpose

The
purpose of this funding announcement is to transform our understanding of the
epigenomic basis of human disease. Applicants will discover and define global
(epigenome-wide) marks or features, and their possible interactions, in
diseased, aged, or otherwise compromised human
primary cells or tissues. Studies using mammalian animal models will be allowed
with appropriate justification addressing reasons why human tissues cannot be
examined for the disease/condition of interest. The goal is to transform our understanding of human disease, aging, or
response to insult by correlating changes in the epigenome with the altered
cellular state. These discovery-based approaches to reveal epigenome-wide
characteristics may also be followed up by epigenetic
approaches that aim to reveal function or significance of target gene regions
or loci identified during the initial mapping activities.

Background

The
organization of DNA into chromatin presents the cell with the opportunity to
use powerful regulatory mechanisms broadly defined as
epigenetics. Increasing evidence demonstrates epigenetic mechanisms are linked
to gene activation, gene silencing and chromosomal instability. Epigenetic
processes act in cell specific, temporally regulated manners to direct normal development, differentiation, organogenesis,
tissue formation, and aging. Epigenetics is an emerging frontier of science
that involves the study of changes in the regulation of gene activity and
expression that are not dependent on gene sequence.
For purposes of this program, epigenetics refers to both heritable changes in
gene activity and expression (in the progeny of cells or of individuals) and
also stable, long-term alterations in the transcriptional potential of a cell
that are not necessarily heritable. While epigenetics
refers to the study of single genes or sets of genes, epigenomics refers to
more global analyses of epigenetic changes across the entire genome.

Epigenetics
is an emerging basic field of science as evidenced by the exponential increase in basic epigenetic research literature
citations observed between 1990 and 2006. A similar pattern of escalating
citations is now being documented with epigenetics and diseases, and multiple
disease focused research grants have been awarded by
the NIH in recent years. Understanding the temporal and tissue specific
regulation of chromatin is fundamental to the study of epigenetics. The precise
organization of DNA into chromatin uniquely directs gene expression via a
series of powerful regulatory mechanisms broadly
defined as epigenetic regulation. Increasing evidence demonstrates epigenetic
mechanisms are linked to gene activation, gene silencing and chromosomal
instability, but little is known about the molecular mechanisms themselves.

Epigenetic regulation of gene transcription apparently plays a
pivotal role in the governance of normal and disease development through
dynamic transcriptional activities from gametogenesis through embryonic and
neonatal stages, and continuing throughout adolescence,
adulthood and elderly stages/old age. Epigenetic research in human health is
rapidly evolving and has reached a critical point where opportunities exist to
make significant inroads in understanding how epigenetically regulated
transcription directs functional processes in
development and across the lifespan as well as in disease states.

Alterations
in normal gene silencing and activation result in inappropriate patterns of
gene expression, adversely affecting phenotypic plasticity and resulting in a broad spectrum of tissue dysfunction and disease outcomes,
including but not limited to multiple cancers, autoimmune diseases,
neurodegenerative disorders, liver diseases, respiratory disorders,
developmental disorders, cardiovascular diseases, and behavioral disorders. The integration of epigenetics with genetics
and environmental influences will be necessary to fully understand mechanisms
of complex human diseases. Epigenetic mechanisms which are responsible for
temporal and tissue specific activation or silencing
of gene transcription include: DNA methylation of CpG islands in promoters and
other regions of the genome; chromatin remodeling and higher order chromatin
structural alterations; post-translational ATP-dependent modifications which
include methylation, acetylation, ubiquitination, and
phosphorylation of histone tail domains; and gene regulation through non-coding
RNAs. There are likely additional epigenetic modifications and regulatory
mechanisms that have not yet been discovered or elucidated.

Normal
development and aging are also directed by epigenetic processes and can be
affected by various environmental exposures resulting in alterations in the
transcriptional potential of a cell or tissue type. This altered gene
expression in many cases is stable and may persist
leading to increased susceptibility to disease later in life and even across
generations.

Epigenetic
research has enormous potential for significantly furthering our understanding
of human health and treatment of disease. Other long term potential benefits of the Roadmap Epigenomics Program include
identification/elucidation of:

Understanding
the molecular basis of human biology and disease is of fundamental importance
to the Institutes, Centers, and Offices of the NIH. Complex biological
processes underlying states of health and diseases,
which involve feedback between many genes and cells, are likely to be driven by
epigenetic changes and responses as well as by allelic variations. Progression
of disease may often be better explained by epigenetic alterations than by mutations. Several well established epigenetic
marks (e.g. DNA methylation or specific histone modifications) are known to
affect gene expression by affecting the transcriptional potential of cells.
Other epigenetic alterations, such as trans-acting
factors, post-translational modifications of particular proteins, and some
non-coding RNAs are more recently discovered, and the mechanisms and
significance of their roles in regulating cellular phenotype are only poorly
understood. Additional, yet undiscovered epigenetic
marks may exist as well, and identification of these novel marks could
significantly advance our understanding of epigenetic regulation underlying
human health and disease. The Discovery of Novel Epigenomic Marks RFA (RFA-RM-07-015/016) is intended to foster the discovery of
novel marks.

The
“epigenome” does not exist in the same sense as the “genome” of a species or an
individual. Rather, many epigenomes or epigenomic
profiles exist. Each one directs a specific gene expression profile and
therefore the phenotype of a cell or tissue, and is highly dynamic as the cell
responds to its environment and takes part in biological processes. For the
purposes of this FOA, an “epigenome” is the
epigenomic profile from a specific cell or tissue type which represents its
biological condition or state (e.g., normal or homeostatic, perturbed in
response to exogenous exposures, abnormal or diseased), defines its transcriptional potential, and provides clues about how epigenetic
processes may regulate cellular function.

This
announcement is intended to encourage the application of global epigenome-wide
approaches to transform our knowledge of how the epigenome defines and contributes to human disease. It requires applicants to
propose projects that employ unbiased, global approaches in human cells (or
with rare exceptions, cells from mammalian models; see below) to correlate
alterations in epigenomic structure/marks with disease,
aging, or environmental perturbation. Following the initial global mapping,
applicants may also propose to conduct epigenetic analyses to reveal the
function or significance of target gene regions or loci identified during the
initial global screen. Because the primary focus of
an application should be the application of global mapping approaches across
the genome, any proposed epigenetic analyses should be considered as follow up
and secondary to the initial global mapping. Thus, applications that propose to focus the initial epigenome-wide mapping on a single
gene, gene set, or restricted genomic region, or on epigenetic marks already
known to be involved in a particular human disease will not be considered
responsive to this FOA.

Thus,
applicants should propose studies using
epigenome-wide approaches in primary cells/tissues that represent compromised,
abnormal or diseased states in humans, and include epigenome-wide analyses in
comparative (control) normal or healthy cells/tissues for the disease under study. Examples of disease-related research areas that
address physiologically compromised, abnormal or diseased states include:

• perturbation due to exogenous exposure
to dietary, chemical, social, or behavioral factors that may contribute to
human disease

Applicants
may propose to map various epigenetic modifications such as but not limited to:
regions or patterns of methylated DNA and/or CpG motifs, histone tail
modifications (e.g., acetylation, phosphorylation, ubiquitination) or other components of chromatin structure and
remodeling, and/or non-coding RNAs such as siRNAs (21-23 nucleotides), PIWI
interacting or piRNAs (26-31 nucleotides), or germ line RNAs (24-29
nucleotides) that may be involved in epigenetic regulation.

Applicants
should propose studies involving human cells and tissues (except under special
circumstances, described below) and provide a rationale for the selection of
cells/tissues for establishing the epigenomic maps. The rationale should
describe how understanding changes in epigenomic
marks or features, and their possible interactions, in perturbed or diseased
states as compared to normal or healthy states will disrupt current paradigms
concerning disease etiology or progression or how it will create new paradigms where none exists.

The
NIH recognizes that insight into human diseases, such as brain-related
disorders, may be restricted to animal models at present because appropriate
human research models are not available. For diseases that cannot be pursued in human models, applicants may propose to work in
mammalian models, but must provide a specific rationale for using an animal
model to further the understanding of human disease because an appropriate
human model is not available.

The
NIH anticipates that cell/tissue systems for the
study of some diseases may not be immediately amenable to global mapping
approaches. Thus, applicants may propose projects whose initial aims involve
the application of global approaches to characterize epigenomic profiles of normal physiology in healthy primary cells/tissues as
a comparison for the disease of interest; however, the proposed aims must
involve global epigenomic mapping in relevant (comparative) abnormal or
diseased cells/tissues by year 3 of the project.

Comparative analyses involving more than one cell/tissue
type, or disease state or process, may also be appropriate. Applicants may
propose to investigate epigenomes in existing (archived) or new human
biospecimens collected as part of other ongoing funded human clinical or epidemiological studies of human disease. Proposals
seeking to initiate new human studies for the purpose of collecting
biospecimens for epigenomic analysis are outside the scope of this funding
announcement. However, the addition of an epigenome-wide
mapping component, funded through this FOA, to an ongoing clinical or
epidemiological study of human disease may be appropriate.

Research
Scope

This
FOA under the NIH Roadmap is intended to lead to fundamentally new paradigms of
disease etiology and progression through
identification of epigenomic contribution to disease processes. The scientific
scope of this FOA is intentionally broad in order to address the collective
research interests of the participating NIH Institutes, Offices and Centers. Because each NIH entity has a unique scientific
purview and set of program goals and initiatives that evolve over time, it is
strongly suggested that all applicants, prior to preparing an application,
consult the appropriate Institute representative, listed below in Section
VII, to obtain current information about each Institute's
program priorities.

Program
Components

This
FOA on the Epigenomics of Human Health and Disease is one component of the
larger Roadmap Epigenomics Program. The purpose of
this funding opportunity is to encourage the application of existing and newly
emerging research knowledge and analysis tools to study of epigenomic
contributions to human disease. Thus, applicants to this FOA are encouraged to utilize the resources being generated by other initiatives
included in the Roadmap Epigenomics Program. For example, the research
knowledge generated by the Reference Epigenome Mapping Centers (REMCs) (RFA-RM-07-013) may serve as relevant “reference”
epigenome data for specific disease-related processes, states or conditions
proposed under this FOA. In addition, investigators funded under this FOA may
propose to engage in collaborative research
activities with investigators funded under the REMCs to provide biospecimens
for analytical services to be conducted by the REMCs.

An
important aspect of the Roadmap Epigenomics Program is the development of an
integrated database. The database will be created and
maintained by the NIH National Center for Biotechnology Information (NCBI), in
collaboration with the Epigenomics Data Analysis and Coordination Center
(EDACC) (RFA-RM-07-014), and will serve as a resource for the
Roadmap Epigenomics Program and other researchers working to unravel the
components of disease and dysfunction in addition to providing important
information about health and normal processes.

To
ensure data obtained from the studies funded under this FOA can be utilized in
the program database, applicants are expected to describe an informatics plan
for processing the primary data to generate a list of the epigenetic marks or
features found under the proposed experimental
conditions. The plan should include a description of how primary data will be
processed and transferred in standardized formats to the EDACC or directly to
the NCBI as specified by the data release principles (see below). It will be essential for each application to demonstrate
expertise in informatics to ensure data can be formatted and transferred to the
NCBI in a format that is consistent with the other components of the Roadmap
Epigenomics Program. Applicants may propose to
utilize the EDACC to perform the data formatting and transfer to NCBI, and if
so, are required to contact the EDACC PI and submit a letter of collaboration
to ensure inclusion of their data in the EDACC activities and make financial
arrangements to provide support for these activities.

Although
individual grants funded under this FOA will be assigned to and managed by a
lead NIH Institute or Center, all the funded projects will be linked
programmatically to each other and to other funded projects in the Roadmap Epigenomics Program to facilitate information
sharing and promote research collaborations.

Summary
of Requirements

Applications
responsive to this FOA should have the potential to dramatically transform our
understanding of the epigenetic basis of one or more
human diseases. In addition to describing how current paradigms concerning
disease processes will be disrupted, responsive applications will:

• Clearly
describe the relevance of the proposed work to a human disease. For some
diseases, applications may initially focus on the
epigenomic basis of an underlying biological process related to disease, but
must address one or more relevant (comparative) human diseases by year 3 of the
project.

• Include a
global epigenome-wide component, but may also include
follow up epigenetic approaches.

• Use human
cells and/or tissues or provide a strong justification for why a mammalian
model is scientifically appropriate. For example, an animal model could be
justified when it would be extremely difficult or
impossible to obtain the appropriate human cells or tissues, such as for some
brain-related research.

• Describe
the informatics plan.

Evaluation

As
part of good program management, NIH assesses the implementation and
effectiveness of its programs using evaluation tools
and techniques. Grantees may be asked to provide information for program
evaluation purposes, both locally and at the national level. Such information
may be used in evaluations of the initiative as well as the “Mid-Course” review
of the entire Roadmap Epigenomics Program. Note that
the Roadmap Epigenomics Program mid-course evaluation will be directed by the
Roadmap Epigenomics Working Group. Applicants are advised to review the
additional details on evaluation that are provided in Section IV.6. Application and Submission Information,
“Other Submission Requirements.”

This
FOA will use theR01 award mechanism. The Project Director/Principal Investigator (PD/PI) will
be solely responsible for planning, directing, and executing the proposed project.

This FOA uses “Just-in-Time” information concepts (see SF424 (R&R)
Application Guide). It also uses the modular as well as the
non-modular budget formats (seehttps://grants.nih.gov/grants/funding/modular/modular.htm).
Specifically, a U.S. organization submitting an application with direct costs
in each year of $250,000 or less (excluding consortium Facilities and
Administrative [F&A] costs) must use the PHS398 Modular Budget component.

U.S. applicants requesting more than
$250,000 in annual direct costs and all Foreign applicants must complete and
submit budget requests using the Research & Related Budget component.

2.
Funds Available

The NIH
intends to commit $8M dollars (total costs), in FY 2009, to fund applications
in response to this FOA.

NIH intends to
fund twelve to sixteen meritorious projects that are responsive to this FOA.

The total
project period for an application submitted in response to this FOA may not
exceed 5 years.

The earliest
anticipated start date for new awards through this announcement is July 2009.

Because the
nature and scope of the proposed research will vary from application to
application, it is anticipated that the size and duration of each award will
also vary.

The total number of R01sawarded
will depend on the number of applications received, their relative scientific
merit, and the availability of NIH Roadmap and Individual Institute and Center funds.

Facilities
and Administrative (F&A) costs requested by consortium participants are not
included in the direct cost limitation. See NOT-OD-05-004.

The decision of whether to
apply for a grant with a single PD/PI or multiple PDs/PIs grant is the
responsibility of the investigators and applicant organizations and should be
determined by the scientific goals of the project. Applications for grants with
multiple PDs/PIs will require additional information, as outlined in the
instructions below. The NIH review criteria for approach, investigators, and environment
have been modified to accommodate applications involving either a single PD/PI
or multiple PDs/PIs. When considering the multiple PD/PI option, please be
aware that the structure and governance of the PD/PI leadership team as well as
the knowledge, skills and experience of the individual PDs/PIs will be factored
into the assessment of the overall scientific merit of the application.
Multiple PDs/PIs on a project share the authority and responsibility for
leading and directing the project, intellectually and logistically. Each
PD/PI is responsible and accountable to the grantee organization, or, as
appropriate, to a collaborating organization, for the proper conduct of the
project or program, including the submission of required reports. For further information
on multiple PDs/PIs, please seehttps://grants.nih.gov/grants/multi_pi.

Applicants
may submit more than one application, provided each application is
scientifically distinct.

Section IV. Application and Submission Information

To
download a SF424 (R&R) Application Package and SF424 (R&R) Application
Guide for completing the SF424 (R&R) forms for this FOA, use the “Apply for
Grant Electronically” button in this FOA or link to http://www.grants.gov/Apply/ and follow
the directions provided on that Web site.

A one-time registration is required for institutions/organizations at both:

The individual(s) designated as
PDs/PIs on the application must be registered also in the NIH eRA Commons. In the case of multiple PDs/PIs, all PDs/PIs must be registered and be assigned
the PI role in the eRA Commons prior to the submission of the application.

Each PD/PI must
hold a PD/PI account in the Commons. Applicants should not share a Commons account for both an Authorized Organization
Representative/Signing Official (AOR/SO) role and a PD/PI role; however, if they have both a
PD/PI role and an NIH Internet Assisted Review (IAR) role, both roles should
exist under one Commons account.

When multiple PDs/PIs are
proposed, all PDs/PIs at the applicant organization must be affiliated with
that organization. PDs/PIs located at another institution need not be
affiliated with the applicant organization, but must be affiliated with their
own organization to be able to access the Commons.

This registration/affiliation must
be done by the AOR/SO or his/her designee who is already registered in the Commons.

Both the PDs/PI(s) and
AOR/SO need separate accounts in the NIH eRA Commons since both are authorized
to view the application image.

Note that if a PD/PI is
also an NIH peer reviewer with an Individual DUNS and CCR registration, that
particular DUNS number and CCR registration are for the individual reviewer
only. These are different than any DUNS number and CCR registration used by an
applicant organization. Individual DUNS and CCR registration should be used
only for the purposes of personal reimbursement and should not be used on any
grant applications submitted to the Federal Government.

Several of the steps of
the registration process could take four weeks or more. Therefore, applicants
should immediately check with their business official to determine whether
their organization/institution is already registered in both Grants.gov and the Commons. The NIH will accept
electronic applications only from organizations that have completed all necessary
registrations.

1. Request Application Information

Applicants must
download the SF424 (R&R) application forms and the SF424 (R&R)
Application Guide for this FOA through Grants.gov/Apply.

Note:
Only the forms package directly attached to a specific FOA can be used. You
will not be able to use any other SF424 (R&R) forms (e.g., sample forms,
forms from another FOA), although some of the "Attachment" files may
be useable for more than one FOA.

Prepare all
applications using the SF424 (R&R) application forms and in accordance with
the SF424 (R&R) Application Guide for this FOA
through Grants.gov/Apply.

The SF424 (R&R) Application
Guide is critical to submitting a complete and accurate application to NIH.
Some fields within the SF424 (R&R) application components, although not
marked as mandatory, are required by NIH (e.g., the “Credential” log-in
field of the “Research & Related Senior/Key Person Profile” component must
contain the PD/PI’s assigned eRA Commons User ID). Agency-specific
instructions for such fields are clearly identified in the Application Guide.
For additional information, see “Frequently Asked Questions – Application
Guide, Electronic
Submission of Grant Applications.”

The SF424 (R&R)
application has several components. Some components are required, others are
optional. The forms package associated with this FOA in Grants.gov/APPLYincludes all applicable components, required and optional. A completed
application in response to this FOA includes the data in the following
components:

Proposed research should provide special opportunities
for furthering research programs through the use of unusual talent, resources,
populations, or environmental conditions in other countries that are not
readily available in the United States (U.S.) or that augment existing U.S. resources.

SPECIAL
INSTRUCTIONS

Applications with
Multiple PDs/PIs

When
multiple PDs/PIs are proposed, NIH requires one PD/PI to be designated as the
"Contact” PI, who will be responsible for all communication between the
PDs/PIs and the NIH, for assembling the application materials outlined below,
and for coordinating progress reports for the project. The contact PD/PI must
meet all eligibility requirements for PD/PI status in the same way as other
PDs/PIs, but has no other special roles or responsibilities within the project
team beyond those mentioned above.

Information
for the Contact PD/PI should be entered in item 15 of the SF424 (R&R) Cover
component. All other PDs/PIs should be listed in the Research &
Related Senior/Key Person component and assigned the project role of
“PD/PI.” Please remember that all PDs/PIs must be registered in the eRA Commons prior to application submission. The Commons ID of each PD/PI must be included in the
“Credential” field of the Research & Related Senior/Key Person
component. Failure to include this data field will cause the application
to be rejected.

All projects
proposing Multiple PDs/PIs will be required to include a new section describing
the leadership plan approach for
the proposed project.

Multiple
PD/PI Leadership Plan: For applications designating multiple PDs/PIs, a new
section of the research plan, entitled “Multiple PD/PI Leadership Plan”
[Section 14 of the Research Plan Component in the SF424 (R&R)], must be
included. A rationale for choosing a multiple PD/PI approach should be
described. The governance and organizational structure of the leadership team
and the research project should be described, and should include communication
plans, process for making decisions on scientific direction, and procedures for
resolving conflicts. The roles and administrative, technical, and
scientific responsibilities for the project or program should be delineated for
the PDs/PIs and other collaborators.

If
budget allocation is planned, the distribution of resources to specific
components of the project or the individual PDs/PIs should be delineated in the
Leadership Plan. In the event of an award, the requested allocations may be
reflected in a footnote on the Notice of Award (NoA).

Applications Involving a
Single Institution

When all PDs/PIs are
within a single institution, follow the instructions contained in the SF424
(R&R) Application Guide.

Applications Involving
Multiple Institutions

When
multiple institutions are involved, one institution must be designated as the
prime institution and funding for the other institution(s) must be requested
via a subcontract to be administered by the prime institution. When submitting
a detailed budget, the prime institution should submit its budget using the
Research & Related Budget component. All other institutions should have
their individual budgets attached separately to the Research & Related
Subaward Budget Attachment(s) Form. See Section 4.8 of the SF424 (R&R)
Application Guide for further instruction regarding the use of the subaward
budget form.

When
submitting a modular budget, the prime institution completes the PHS398 Modular
Budget component only. Information concerning the consortium/subcontract
budget is provided in the budget justification. Separate budgets for each
consortium/subcontract grantee are not required when using the Modular budget
format. See Section 5.4 of the Application Guide for further instruction
regarding the use of the PHS398 Modular Budget component.

Applications Involving Federal Agencies

The requests from federal agencies, including the NIH
intramural program, will not include any salary and related fringe benefits for
career, career conditional or other federal employees (civilian or uniformed
service) with permanent appointments under existing position ceilings or any
costs related to administrative or facilities support (equivalent to Facilities
and Administrative costs).

In general, the budget requests will be limited to the
incremental costs required for carrying out the proposed work. These costs may
include salary for staff to be specifically hired under a temporary appointment
for the project, consultant costs, equipment, supplies, travel, and other items
typically listed under Other Expenses. While support for extramural
collaborators may be requested in a separate grant application, funds can be
requested for services by an external investigator or contractor as a
subcontract/consortium including the applicable indirect (F&A costs) of the
contractor/collaborating institution.

Justification must be provided for all requested
support and for the Federal employees who will be committed to the project
although no funds are requested in the application.

Applicants should indicate the number of person-months
devoted to the project, even if no funds are requested for salary and fringe
benefits.

Prospective
applicants are asked to submit a letter of intent that includes the following
information:

Descriptive title of proposed research.

Name, address, and telephone number of the
PD(s)/PI(s).

Names of other key personnel.

Participating institutions.

Number and title of this funding opportunity.

Although
a letter of intent is not required, is not binding, and does not enter into the
review of a subsequent application, the information that it contains allows IC
staff to estimate the potential review workload and plan the review.

In order to expedite the
review, applicants are requested to notify the NIAAAReferral Office by email weis@mail.nih.govwhen the application has been
submitted. Please include the FOA number and title, PD/PI name, and
title of the application.

3.C.
Application Processing

Applications may be submitted on or after the opening date and must be
successfully received by Grants.gov no later than 5:00 p.m. local time (of the applicant
institution/organization) on the application due date(s). (See Section IV.3.A. for all dates.) If an application is not submitted by the due date(s)
and time, the application may be delayed in the review process or not reviewed.

Once an application package has been successfully
submitted through Grants.gov, any errors have been addressed, and the assembled
application has been created in the eRA Commons, the PD/PI and the Authorized Organization
Representative/Signing Official (AOR/SO) have two weekdays (Monday – Friday,
excluding Federal holidays) to view the application image to determine if any
further action is necessary.

If everything is acceptable, no
further action is necessary. The application will automatically
move forward to the Division of Receipt and Referral in the Center for
Scientific Review for processing after two weekdays, excluding Federal holidays.

Prior to the submission deadline, the
AOR/SO can “Reject” the assembled application and submit a
changed/corrected application within the two-day viewing window. This
option should be used if it is determined that some part of the
application was lost or did not transfer correctly during the submission
process, the AOR/SO will have the option to “Reject” the application and
submit a Changed/Corrected application. In
these cases, please contact the eRA Help Desk to ensure that the issues
are addressed and corrected. Once rejected, applicants should follow the
instructions for correcting errors in Section 2.12, including the
requirement for cover letters on late applications. The
“Reject” feature should also be used if you determine that warnings are
applicable to your application and need to be addressed now. Remember,
warnings do not stop further application processing. If an application
submission results in warnings (but no errors), it will automatically move
forward after two weekdays if no action is taken. Some warnings may
need to be addressed later in the process.

If
the two-day window falls after the submission deadline, the AOR/SO will have
the option to “Reject” the application if, due to an eRA Commons or Grants.gov
system issue, the application does not correctly reflect the submitted
application package (e.g., some part of the application was lost or didn’t
transfer correctly during the submission process). The AOR/SO should first
contact the eRA Commons Helpdesk to confirm the system error, document the issue, and determine the best course
of action. NIH will not penalize the applicant for an eRA Commons or Grants.gov system issue.

If
the AOR/SO chooses to “Reject” the image after the submission deadline for a
reason other than an eRA Commons or Grants.gov system failure, a
changed/corrected application still can be submitted, but it will be subject to
the NIH
late policy guidelines and may not be accepted. The reason for this delay
should be explained in the cover letter attachment.

Both
the AOR/SO and PD/PI will receive e-mail notifications when the application is
rejected or the application automatically moves forward in the process after
two weekdays.

Upon receipt, applications will be evaluated for
completeness by the CSR and responsiveness by the Roadmap Epigenomics Working Group. Incomplete
and non-responsive applications will not be reviewed.

There
will be an acknowledgement of receipt of applications from Grants.gov and the Commons. The submitting AOR/SO
receives the Grants.gov acknowledgments. The AOR/SO and the PI receive Commons acknowledgments. Information related to the assignment of an application to a Scientific
Review Group is also in the Commons.

Note: Since email can be
unreliable, it is the responsibility of the applicant to check periodically on
the application status in the Commons.

The
NIH will not accept any application in response to this funding opportunity
that is essentially the same as one currently pending initial review, unless
the applicant withdraws the pending application. However, when a previously
unfunded application, originally submitted as an investigator-initiated
application, is to be submitted in response to a funding opportunity, it is to
be prepared as a NEW application. That is, the application for the funding
opportunity must not include an “Introduction” describing the changes and
improvements made, and the text must not be marked to indicate the changes from
the previous unfunded version of the application.

All NIH awards are
subject to the terms and conditions, cost principles, and other considerations
described in the NIH Grants Policy Statement.

Pre-award
costs are allowable. A grantee may, at its own risk and without NIH prior
approval, incur obligations and expenditures to cover costs up to 90 days
before the beginning date of the initial budget period of a new or renewal
award if such costs: 1) are necessary to conduct the project, and 2) would be
allowable under the grant, if awarded, without NIH prior approval. If specific
expenditures would otherwise require prior approval, the grantee must obtain
NIH approval before incurring the cost. NIH prior approval is required for any
costs to be incurred more than 90 days before the beginning date of the initial
budget period of a new or renewal award.

The incurrence of pre-award costs in anticipation of a
competing or non-competing award imposes no obligation on NIH either to make
the award or to increase the amount of the approved budget if an award is made
for less than the amount anticipated and is inadequate to cover the pre-award
costs incurred. NIH expects the grantee to be fully aware that pre-award costs
result in borrowing against future support and that such borrowing must not
impair the grantee's ability to accomplish the project objectives in the
approved time frame or in any way adversely affect the conduct of the project
(see theNIH
Grants Policy Statement).

The
applicant organization must include its DUNS number in its Organization Profile
in the eRA Commons. This DUNS number must match the DUNS number provided at CCR
registration with Grants.gov. For
additional information, see “Frequently Asked Questions – Application Guide, Electronic
Submission of Grant Applications.”

Supplementary
Instructions:

The
following exceptions to the general R01 instructions will apply for this FOA:

Biosketches:
Each biosketch is limited to four pages. The number of publications cited in the PI’s biosketch is limited to ten or
fewer items. PIs should cite their most relevant publications and those that
illustrate their ability to perform epigenomic analyses. Publications that
demonstrate exceptional innovation and significance
need not be related conceptually to what the PI is proposing in this
application. Following each cited publication, the applicant should very
briefly summarize the findings or achievements described in the publication
that demonstrate relevance to the proposed work, if
not apparent in the title. Summaries should not exceed 60 words each.

Research
plan: The research plan is limited to 12 pages. It should be self-contained,
since appendices and updates are not allowed. Omit the Specific Aims, Background and Significance, and Preliminary Studies sections. In
the Research Design and Methods section, the applicant should address the
following six points in a single PDF file with a separate subheading for each
point. Applications will be evaluated by review
panels that represent a diversity of scientific interests and expertise.
Therefore, jargon must be avoided. Explain the challenge, the potential impact,
and the approach in language that scientists with broad expertise can
understand.

1.
The Challenge: What is the disease or condition that
will be studied, and what is the hypothesis to be tested concerning epigenomic
mechanisms underlying this disease/condition? How will the work disrupt the
standard paradigm or create a paradigm where none exists?

2. The Potential Impact: How will the results transform our
understanding of this disease/condition? How broad is the potential impact?
Which community will be affected? What is the size of that community?

3.
The Approach (limit, four pages): What are the epigenomic
marks to be analyzed, and how will they be mapped across the genome and of
which cells? Provide enough information that reviewers can determine what, in
general, you are proposing to do, but do not include a detailed experimental
plan. If your methodology is novel, what is
unconventional and exceptionally innovative about your approach? How does your
approach differ from what other investigators have attempted to do? If you plan
to use mammalian cells, provide strong justification: why can human cells not be used to understand the disease of interest?

4.
The Appropriateness of Roadmap: Why is the proposed research uniquely suited to
the stated goals of the NIH Roadmap Epigenomics initiative? How does the
proposed research differ from what is being done in
your and other laboratories?

5.
The Likelihood of Success: Briefly describe your prior efforts in the area of
epigenomic mapping. What were the technologies used in your prior studies, how
comprehensive have prior efforts been in determining the epigenomic structure of particular cells, and how do they
compare to the current application?

6.
Timeline (limit, half a page): Provide a timeline for the proposed research. To
facilitate evaluation of progress reports, describe when you anticipate that essential components of the project (e.g., acquisition of
samples, optimization of protocols, critical experiments to verify the
hypothesis, validation of novel tools or techniques) will be completed.

Literature
Cited: limited to one page. Note that the 12 page
limit for the Research Plan does not include the Literature Cited section
(separate Pdf.).

Appendix:
not allowed

No
updates will be accepted.

Data
Sharing:

To
accelerate progress in the field of epigenomics, grantees will be expected to
participate actively and openly in at least one
grantee meeting per year. Substantial information sharing is critical to the
program, so how an applicant plans to achieve this would be considered as a
term and condition of the award; failure to openly share information will be considered in continued funding consistent
with achieving the goals of the program. It is understood that some information
developed under the grants will be proprietary and cannot be shared immediately
without damaging the commercialization potential of
the scientific discovery or in some cases jeopardizing the protection of human
subjects. Applicants should describe their plans for participating in the
grantee meetings and for managing any appropriate intellectual property
concerns in the context of those meetings and other
opportunities for information sharing in the Other Research Plan Sections
under Resource Sharing Plan(s) attachments section. Other investigators in the field
(i.e., not supported under this program) may be invited to participate in these meetings, but their agreement to share
information substantially will be a prerequisite to their participation.
Applicants should budget for travel funds for the PD/PI and one additional lead
investigator to attend the annual meeting.

Resource Sharing Plan(s)

NIH considers
the sharing of unique research resources developed through NIH-sponsored
research an important means to enhance the value and further the advancement of
the research. When resources have been developed with NIH funds and the
associated research findings published or provided to NIH, it is important that
they be made readily available for research purposes to qualified individuals
within the scientific community. If the final
data/resources are not amenable to sharing, this must be explained in the
Resource Sharing section of the application (see https://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.)

(b) Sharing Model Organisms: Regardless of
the amount requested, all applications where the development of model organisms
is anticipated are expectedto include a description of a
specific plan for sharing and distributing unique model organisms and related
resources or state appropriate reasons why such sharing is restricted or not
possible (see Sharing
Model Organisms Policy, and NOT-OD-04-042.)

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount
requested, applicants seeking funding for a genome-wide association
study are expected to provide a plan for submission of GWAS data to the
NIH-designatedGWAS data repository, or provide an appropriate
explanation why submission to the repository is not possible. A
genome-wide association study is defined as any study of genetic variation
across the entire genome that is designed to identify genetic associations with
observable traits (e.g., blood pressure or weight) or the presence or absence
of a disease or condition. For further information see Policy for Sharing
of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies
(go to NOT-OD-07-088, and https://grants.nih.gov/grants/gwas/.)

The adequacy of the resources
sharing plan and any related data sharing plan will be considered by Program staff of
the funding organization when making recommendations about funding
applications. The effectiveness of the resource sharing will be evaluated as
part of the administrative review of each Non-Competing Grant Progress Report
(PHS 2590). See Section VI.3. Award
Administration Information, “Reporting.”

As the Roadmap Epigenomics Program
is a community resource program, NIH expects that not only data, but also
resources generated during the course of the program should be made rapidly available to the research community and that
sharing plans should follow the same principles and spirit as the proposed
rapid data release policy. The applicant should provide specific plans for
resource sharing and distribution in the application. The reasonableness of the data sharing plan will be assessed by the reviewers.
If resource sharing and/or data sharing are not possible, perhaps due to
restrictions inherent to the informed consent process or concerns that human
subjects’ privacy could be compromised, the
application should describe why sharing is not possible. However, reviewers
will not factor the proposed resources sharing plan into the determination of
scientific merit or the priority score. The adequacy of the resources sharing
plans will be considered by the funding organization
when making recommendations about funding applications. The presence of a
resources sharing plan will be part of the terms and conditions of the award.
The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant
Progress Report (PHS 2590, https://grants.nih.gov/grants/funding/2590/2590.htm). See Section VI.3. Award Administration
Information, “Reporting.”

Technology and Data Sharing
Overview

This initiative is part of a
broader program in Epigenomics funded as part of the NIH Roadmap. In order to
fulfill requirements for oversight of the Roadmap Epigenomics
Program as a whole, NIH staff may need to present status reports on individual
initiatives to coincide with NIH Office of the Director timeframes. Thus, in
addition to the annual Non-Competing Grant Process Report (PHS 2590, https://grants.nih.gov/grants/funding/2590/2590.htm), awardees may be required to submit additional progress
updates at a time to be determined by NIH. Program staff will use information
from reports, site visits, etc. to evaluate each
grantee’s progress and the success of the overall program. Progress will also
be evaluated with the assistance of external advisors at the annual meeting and
at the mid-course review of the entire Roadmap Epigenomics Program (see “Management and Evaluation” below).

Management and Evaluation

The project management team will
evaluate the grants through annual progress reports and through annual All
Hands Roadmap Epigenomics Program meetings starting in year 1 of the award. PIs
of funded projects will be required to attend at
least one grantee meeting per year for project evaluation and to facilitate
technology transfer to the other components of the Roadmap Epigenomics Program.
The annual meeting will include program staff, external advisors, and PIs from all funded awards in the Roadmap
Epigenomics Program.

Sharing with other Roadmap
Epigenomics Program Grantees

To accelerate progress in the
field of epigenomics, grantees will be expected to participate actively and
openly in at least one grantee meeting per year.
Substantial information sharing is critical to the program, so how an applicant
plans to achieve this would be considered as a term and condition of the award;
failure to openly share information will be considered in continued funding consistent with achieving the goals of the
program. It is understood that some information developed under the grants will
be proprietary and might not be shared immediately without damaging the
potential patenting or commercialization opportunities,
or compromising the protection of human subjects. Applicants should describe their
plans for participating in the grantee meetings and for managing any
appropriate intellectual property concerns in the context of those meetings and
other opportunities for information sharing in the Other
Research Plan Sections under Resource Sharing Plan(s) attachments section If resource sharing or data sharing is not possible,
perhaps due to restrictions inherent to the informed consent process or
concerns that human subjects’ privacy could be
compromised, the application should describe why sharing is not possible.
Other investigators in the field (i.e., not supported under this program) may
be invited to participate in these meetings, but their agreement to share information substantially will be a prerequisite to their
participation. Applicants should request travel funds in their budgets for the
principal investigator and up to one additional lead investigator to attend the
annual meeting.

Intellectual Property Management Plan

Certain research plans will
require collaboration and coordination among investigators at different
institutions, some of whom may not be NIH funding recipients and may have
pre-existing intellectual property obligations to third parties. It is anticipated that commercial embodiments of the results
of such research may incorporate single inventions shared by several
institutions, or multiple inventions each from a separate institution.
Therefore, prior to funding, grant applicants are expected to address, for example, how they will coordinate patent
prosecution and licensing activities, if necessary to enable a licensee to
access the bundle of intellectual property needed to take a product to market
on commercially viable terms. Suggested strategies
include: (1) assigning intellectual property rights to related inventions to an
invention management firm; (2) designating one organization to take the lead on
patenting and licensing related inventions; and (3) agreeing in advance that if
multiple parties are to independently license-related
inventions, the total of stacked royalties will not exceed a predetermined
percentage rate. The technology transfer/ intellectual property
management/licensing officer or equivalent of the PI's institution is expected to submit an intellectual property management plan,
including at least those elements above. Alternatives to the suggested
strategies, which accomplish the same goals, will be considered. Intellectual
property management plans are a just-in-time requirement
and do not need to be included in the grant application but plans will be
required before a grant can be awarded. The applicant's institution should
avoid exclusively licensing those inventions that are research tools unless
either: (1) the field of use of the exclusive license
is restricted to commercial use; or (2) the exclusive licensee will make the
research tool available on reasonable terms. Applicants are directed to the NIH
policy on the dissemination of biological research resources (“research tools”) at https://grants.nih.gov/grants/intell-property_64FR72090.pdf.

After completion of the initial
review, NIH program staff will be responsible for any additional administrative review of the plan for sharing data. The adequacy of
the data sharing plan, or explanation for why data sharing is not possible,
will be considered by program staff of the funding organization when making
recommendations about funding applications. The final
accepted data sharing plan will become a term and condition of the award. The
effectiveness of the data sharing will be evaluated as part of the
administrative review of each non-competing Grant Progress Report (PHS 2590, https://grants.nih.gov/grants/funding/2590/2590.htm).

Foreign Applications
(Non-Domestic [non-U.S.] Entities)

Indicate how the proposed project has specific
relevance to the mission and objectives of the NIH/IC and has the potential for
significantly advancing the health sciences in the United States.

Section V. Application Review Information

1.
Criteria

Only
the review criteria described below will be considered in the review process.

2.
Review and Selection Process

Applications that are complete
and responsive to this FOA will be evaluated for scientific and technical merit
by an appropriate peer review group convened by the Center for
Scientific Review (CSR) in accordance with the review criteria stated below.

As part of the scientific peer review, all applications will:

Undergo a
selection process in which only those applications deemed to have the
highest scientific and technical merit, generally the top half of
applications under review, will be discussed and assigned a priority
score;

Receive a
written critique; and

Receive a
second level of review by Advisory Councils of the NIH.

Applications
submitted in response to this FOA will compete for available funds with all
other recommended applications submitted in response to this FOA. The following will be
considered in making funding decisions:

Scientific
merit of the proposed project as determined by peer review.

Availability
of funds.

Relevance
of the proposed project to program priorities.

The quality of the plan to
share data and resources, and to make them available to the research
community.

The goals of NIH supported research are to advance
our understanding of biological systems, to improve the control of disease, and
to enhance health. In their written critiques, reviewers will be asked to
comment on each of the following criteria in order to judge the likelihood that
the proposed research will have a substantial impact on the pursuit of these
goals.

Significance and innovation will be the primary
determinants of the score. The approach will be evaluated for general
feasibility. An application will score poorly if it is clear that the proposed
methodology has no probability at all of being successful, either because it is
inherently illogical or because the same approach has already been attempted
and shown not to be feasible. Neither unavoidable risk, which is intrinsic to
novel and innovative approaches, nor lack of preliminary data will preclude an
application receiving an outstanding priority score.

Significance: Does this study address an important problem? If the
aims of the application are achieved, how will scientific knowledge or clinical
practice be advanced? What will be the effect of these studies on the concepts,
methods, technologies, treatments, services, or preventative interventions that
drive this field? How
important is the problem or hypothesis? If the effort is successful, how
significant will the impact be and how broad is the community that will be
affected? How will scientific knowledge or clinical
practice be transformed? What will be the effect of these studies on the
concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field? Does the application address the goals and
objectives outlined in the RFA; that is, does the
proposed work have the potential to transform our understanding of the
epigenomic components of human disease?

Innovation:Is the project original and innovative? For example: Does
the project challenge existing paradigms or clinical practice; address an
innovative hypothesis or critical barrier to progress in the field? Does the
project develop or employ novel concepts, approaches, methodologies, tools, or
technologies for this area? Does the project
provide an innovative way to think of disease? If the
project is successful, will it represent a transformative step in our
understanding of disease? Will existing paradigms be altered and/or will new
paradigms be created?

Approach:Are the conceptual or clinical
framework, design, methods, and analyses adequately developed, well integrated,
well reasoned, and appropriate to the aims of the project? Does the applicant
acknowledge potential problem areas and consider alternative tactics? For applications designating
multiple PDs/PIs, is the leadership approach, including the designated roles
and responsibilities, governance, and organizational structure, consistent with
and justified by the aims of the project and the expertise of each of the
PDs/PIs?Does the applicant provide a rationale for the selection of
cells/tissues that is compelling for the disease/condition of interest? Does
the applicant propose to work in human cells/tissues or provide a specific
rationale for using a mammalian animal model because an appropriate human model is not available? Is the experimental plan
logical such that there is at least some likelihood that the project will
succeed? Does the applicant identify adequate informatics expertise and include
evidence and assurances that a working relationship
with the REMCs will be in place so that all data obtained through the study
will be formatted in a manner that is consistent with the Roadmap Epigenomics
Mapping Centers (REMCs)?

Investigators:Are the PD(s)/PI(s) and other key personnel appropriately
trained and well suited to carry out this work? Is the work proposed
appropriate to the experience level of the principal investigator and other
researchers? Do(es) the PD(s)/PI(s) and investigative team bring complementary
and integrated expertise to the project (if applicable)?

Environment: Do(es) the scientific environment(s) in which the
work will be done contribute to the probability of success? Do the proposed studies benefit
from unique features of the scientific environment, or subject populations, or employ critical collaborative
arrangements (such as the arrangements with the EDACC and/or REMCs)? Is there evidence of institutional
support?

2.A.
Additional Review Criteria

In addition to
the above criteria, the following items will continue to be considered in the
determination of scientific merit and the rating:

Protection
of Human Subjects from Research Risk: The involvement of human
subjects and protections from research risk relating to their participation in
the proposed research will be assessed. See the “Human Subjects Sections”
of the PHS398 Research Plan component of the SF424 (R&R).

Inclusion of Women, Minorities and Children in Research: The adequacy of
plans to include subjects from both genders, all racial and ethnic groups (and
subgroups), and children as appropriate for the scientific goals of the
research will be assessed. Plans for the recruitment and retention of subjects
will also be evaluated. See the “Human Subjects Sections” of the PHS398
Research Plan component of the SF424 (R&R)

Care and Use of Vertebrate Animals in Research: If vertebrate animals
are to be used in the project, the adequacy of the plans for their care and use
will be assessed. See the “Other Research Plan Sections” of the PHS398 Research
Plan component of the SF424 (R&R).

Biohazards: If materials or procedures are proposed that are potentially
hazardous to research personnel and/or the environment, determine if the
proposed protection is adequate.

2.B. Additional Review Considerations

Budget and
Period of Support: The reasonableness of the proposed budget and the
appropriateness of the requested period of support in relation to the proposed
research may be assessed by the reviewers. The priority score should not be
affected by the evaluation of the budget.

Applications from Foreign Organizations: Whether the project presents special opportunities
for furthering research programs through the use of unusual talent, resources,
populations, or environmental conditions in other countries that are not
readily available in the United States or that augment existing U.S. resources will be assessed.

2.C. Resource Sharing Plan(s)

When relevant,
reviewers will be instructed to comment on the reasonableness of the following
Resource Sharing Plans, or the rationale for not sharing the following types of
resources. However, reviewers will not factor the proposed resource sharing
plan(s) into the determination of scientific merit or priority score. Program
staff within the IC will be responsible for monitoring the resource sharing.

A formal notification
in the form of a Notice of Award (NoA) will be provided to the applicant
organization. The NoA signed by the grants management officer is the
authorizing document. Once all administrative and programmatic issues have been
resolved, the NoA will be generated via email notification from the awarding
component to the grantee business official.

Selection of an
application for award is not an authorization to begin performance. Any costs
incurred before receipt of the NoA are at the recipient's risk. These costs may
be reimbursed only to the extent considered allowable pre-award costs. See Section IV.5. “Funding Restrictions.”

2.
Administrative and National Policy Requirements

An NIH Program Official from one or more
of the participating NIH ICs will be assigned to each funded application and
will assume responsibility for normal stewardship of the awards. The various Program Officials with responsibility for
managing individual applications funded under this initiative will work in
concert with one another and with members of the Roadmap Epigenomics Working
Group to assist with convening regular grantees meetings
of the funded PIs, and promote data sharing and collaboration across funded
investigators of all components of the Roadmap Epigenomics Program.

A final
progress report, invention statement, and Financial Status Report are required
when an award is relinquished when a recipient changes institutions or when an
award is terminated.

Section VII. Agency Contacts

We
encourage your inquiries concerning this funding opportunity and welcome the
opportunity to answer questions from potential applicants. Inquiries may fall
into three areas: scientific/research (program), peer review, and financial or
grants management issues:

Human Subjects
Protection:Federal regulations (45 CFR 46) require that
applications and proposals involving human subjects must be evaluated with
reference to the risks to the subjects, the adequacy of protection against
these risks, the potential benefits of the research to the subjects and others,
and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety
Monitoring Plan:Data and safety monitoring is required for all types
of clinical trials, including physiologic toxicity and dose-finding studies
(Phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative
trials (Phase III). Monitoring should be commensurate with risk. The
establishment of data and safety monitoring boards (DSMBs) is required for
multi-site clinical trials involving interventions that entail potential risks
to the participants (“NIH Policy for Data and Safety Monitoring,” NIH Guide
for Grants and Contracts, https://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:Investigators submitting an NIH application seeking
$500,000 or more in direct costs in any single year are expected to include a
plan for data sharing or state why this is not possible (https://grants.nih.gov/grants/policy/data_sharing).Investigators should seek guidance from their
institutions, on issues related to institutional policies and local
institutional review board (IRB) rules, as well as local, State and Federal
laws and regulations, including the Privacy Rule. Reviewers will consider the
data sharing plan but will not factor the plan into the determination of the
scientific merit or the priority score.

Policy for Genome-Wide
Association Studies (GWAS):NIH is interested in advancing genome-wide association
studies (GWAS) to identify common genetic factors that influence health and disease
through a centralized GWAS data repository. For the purposes of this policy, a
genome-wide association study is defined as any study of genetic variation
across the entire human genome that is designed to identify genetic
associations with observable traits (such as blood pressure or weight), or the
presence or absence of a disease or condition. All applications, regardless of
the amount requested, proposing a genome-wide association study are expected to
provide a plan for submission of GWAS data to the NIH-designated GWAS data
repository, or provide an appropriate explanation why submission to the
repository is not possible. Data repository management (submission and access)
is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted
Genome-Wide Association Studies, NIH Guide NOT-OD-07-088.
For additional information, see https://grants.nih.gov/grants/gwas/

Sharing of Model Organisms:NIH is committed to support efforts that encourage
sharing of important research resources including the sharing of model
organisms for biomedical research (see https://grants.nih.gov/grants/policy/model_organism/index.htm).
At the same time the NIH recognizes the rights of grantees and contractors to
elect and retain title to subject inventions developed with Federal funding
pursuant to the Bayh-Dole Act (see the NIH
Grants Policy Statement. Beginning October 1, 2004, all investigators
submitting an NIH application or contract proposal are expected to include in
the application/proposal a description of a specific plan for sharing and
distributing unique model organism research resources generated using NIH
funding or state why such sharing is restricted or not possible. This will
permit other researchers to benefit from the resources developed with public
funding. The inclusion of a model organism sharing plan is not subject to a
cost threshold in any year and is expected to be included in all applications
where the development of model organisms is anticipated.

Access to Research Data through the Freedom of
Information Act:The Office of Management and Budget (OMB) Circular
A-110 has been revised to provide access to research data through the Freedom
of Information Act (FOIA) under some circumstances. Data that are: (1) first
produced in a project that is supported in whole or in part with Federal funds;
and (2) cited publicly and officially by a Federal agency in support of an action
that has the force and effect of law (i.e., a regulation) may be accessed
through FOIA. It is important for applicants to understand the basic scope of
this amendment. NIH has provided guidance at https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this funding opportunity in a
public archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application should
include a description of the archiving plan in the study design and include
information about this in the budget justification section of the application.
In addition, applicants should think about how to structure informed consent
statements and other human subjects procedures given the potential for wider
use of data collected under this award.

Inclusion of Women And Minorities in Clinical Research:It is the policy of the NIH that women and members of
minority groups and their sub-populations must be included in all NIH-supported
clinical research projects unless a clear and compelling justification is
provided indicating that inclusion is inappropriate with respect to the health
of the subjects or the purpose of the research. This policy results from the
NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All
investigators proposing clinical research should read the "NIH Guidelines
for Inclusion of Women and Minorities as Subjects in Clinical Research” (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines is available at https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical
research; updated racial and ethnic categories in compliance with the new OMB
standards; clarification of language governing NIH-defined Phase III clinical
trials consistent with the SF424 (R&R) application; and updated roles and
responsibilities of NIH staff and the extramural community. The policy
continues to require for all NIH-defined Phase III clinical trials that: a) all
applications or proposals and/or protocols must provide a description of plans
to conduct analyses, as appropriate, to address differences by sex/gender
and/or racial/ethnic groups, including subgroups if applicable; and b)
investigators must report annual accrual and progress in conducting analyses,
as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:The NIH maintains a policy that children (i.e.,
individuals under the age of 21) must be included in all clinical research,
conducted or supported by the NIH, unless there are scientific and ethical
reasons not to include them. All investigators proposing research involving
human subjects should read the "NIH Policy and Guidelines" on the
inclusion of children as participants in research involving human subjects (https://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:NIH policy requires education on the protection of
human subject participants for all investigators submitting NIH applications
for research involving human subjects and individuals designated as key
personnel. The policy is available at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):Criteria for Federal funding of research on hESCs can
be found at http://stemcells.nih.gov/index.asp and at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.
Only research using hESC lines that are registered in the NIH Human Embryonic
Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov/). It is the responsibility
of the applicant to provide in the project description and elsewhere in the
application as appropriate, the official NIH identifier(s) for the hESC line(s)
to be used in the proposed research. Applications that do not provide this
information will be returned without review.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy, investigators
funded by the NIH must submit or have submitted for them to the National
Library of Medicine’s PubMed Central (see http://www.pubmedcentral.nih.gov/), an
electronic version of their final, peer-reviewed manuscripts upon acceptance
for publication, to be made publicly available no later than 12 months after
the official date of publication. The NIH Public Access Policy is
available at (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html).For more information, see the Public
Access webpage at http://publicaccess.nih.gov/.

Standards for Privacy of Individually Identifiable Health Information:The Department of Health and Human Services (HHS)
issued final modification to the "Standards for Privacy of Individually
Identifiable Health Information", the "Privacy Rule", on August
14, 2002. The Privacy Rule is a federal regulation under the Health Insurance
Portability and Accountability Act (HIPAA) of 1996 that governs the protection
of individually identifiable health information, and is administered and
enforced by the HHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of
the Privacy Rule reside with the researcher and his/her institution. The OCR
website (http://www.hhs.gov/ocr/)
provides information on the Privacy Rule, including a complete Regulation Text
and a set of decision tools on "Am I a covered entity?" Information
on the impact of the HIPAA Privacy Rule on NIH processes involving the review,
funding, and progress monitoring of grants, cooperative agreements, and
research contracts can be found at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs
in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding
must be self-contained within specified page limitations. For publications listed
in the appendix and/or Progress report, Internet addresses (URLs) or PubMed
Central (PMC) submission identification numbers must be used for publicly
accessible on-line journal articles. Publicly accessible on-line journal
articles or PMC articles/manuscripts accepted for publication that are directly
relevant to the project may be included only as URLs or PMC
submission identification numbers accompanying the full reference in either
the Bibliography & References Cited section, the Progress Report Publication
List section, or the Biographical Sketch section of the NIH grant application.
A URL or PMC submission identification number citation may be repeated in each
of these sections as appropriate. There is no limit to the number of URLs or
PMC submission identification numbers that can be cited.

Healthy People 2010:The Public Health Service (PHS) is committed to
achieving the health promotion and disease prevention objectives of
"Healthy People 2010," a PHS-led national activity for setting
priority areas. This FOA is related to one or more of the priority areas.
Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:This program is described in the Catalog of Federal
Domestic Assistance at http://www.cfda.gov/ and is not
subject to the intergovernmental review requirements of Executive Order 12372.
Awards are made under the authorization of Sections
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284)
and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92. All
awards are subject to the terms and conditions, cost principles, and other
considerations described in the NIH Grants
Policy Statement.

The PHS strongly encourages all grant recipients to
provide a smoke-free workplace and discourage the use of all tobacco products.
In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits
smoking in certain facilities (or in some cases, any portion of a facility) in
which regular or routine education, library, day care, health care, or early
childhood development services are provided to children. This is consistent
with the PHS mission to protect and advance the physical and mental health of
the American people.

Loan Repayment Programs:NIH encourages applications for educational loan
repayment from qualified health professionals who have made a commitment to
pursue a research career involving clinical, pediatric, contraception,
infertility, and health disparities related areas. The LRP is an important
component of NIH's efforts to recruit and retain the next generation of
researchers by providing the means for developing a research career unfettered
by the burden of student loan debt. Note that an NIH grant is not required for
eligibility and concurrent career award and LRP applications are encouraged.
The periods of career award and LRP award may overlap providing the LRP
recipient with the required commitment of time and effort, as LRP awardees must
commit at least 50% of their time (at least 20 hours per week based on a 40
hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov/.